Identification of probe-quality degraders for Poly(ADP-ribose) polymerase-1 (PARP-1).
J Enzyme Inhib Med Chem
; 35(1): 1606-1615, 2020 Dec.
Article
em En
| MEDLINE
| ID: mdl-32779949
ABSTRACT
Poly(ADP-ribose) polymerase-1 (PARP-1), a critical DNA repair enzyme in the base excision repair pathway, has been pursued as an attractive cancer therapeutic target. Intervention with PARP-1 has been proved to be more sensitive to cancer cells carrying BRCA1/2 mutations. Several PARP-1 inhibitors have been available on market for the treatment of breast, ovarian and prostatic cancer. Promisingly, the newly developed proteolysis targeting chimaeras (PROTACs) may provide a more potential strategy based on the degradation of PARP-1. Here we report the design, synthesis, and evaluation of a proteolysis targeting chimaera (PROTAC) based on the combination of PARP-1 inhibitor olaparib and the CRBN (cereblon) ligand lenalidomide. In SW620 cells, our probe-quality degrader compound 2 effectively induced PARP-1 degradation which results in anti-proliferation, cells apoptosis, cell cycle arresting, and cancer cells migratory inhibition. Thus, our findings qualify a new chemical probe for PARP-1 knockdown.
Palavras-chave
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Inibidores de Poli(ADP-Ribose) Polimerases
/
Poli(ADP-Ribose) Polimerase-1
/
Antineoplásicos
Tipo de estudo:
Diagnostic_studies
/
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
J Enzyme Inhib Med Chem
Assunto da revista:
BIOQUIMICA
/
QUIMICA
Ano de publicação:
2020
Tipo de documento:
Article